ABSTRACT
PURPOSE: The options for improving the chemotherapeutic regimen consisting of bolus plus infusion of 5-fluorouracil (5-FU) include omitting the 5-FU bolus injection. We examined the effects of a 5-FU bolus injection on the activity of dihydropyrimidine dehydrogenase (DPD), which is the first and rate-limiting enzyme of 5-FU catabolism, in rats. METHODS: The rats were divided into three groups, and then continuous infusion (50 mg/m(2)/h) for 4 h was started with a bolus injection of saline, 20 mg/kg 5-FU, or 60 mg/kg 5-FU. Plasma 5-FU, uracil (Ura), dihydrouracil (UH2) levels, and hepatic DPD activity were determined after administration of 5-FU. RESULTS: The half-life after the end of the infusion (t 1/2, 4-8 h) of 5-FU in the rats given the bolus injection was significantly longer than in those that had been given saline, and it increased with increasing 5-FU bolus injection dosage (r = 0.801, p < 0.01). The plasma UH2/Ura ratio, an indirect biomarker of hepatic DPD activity, tended to be lower in the rats that had received a 5-FU bolus injection than in those that had not, and it remained low after infusion ended. The hepatic DPD activity in rats that had received a 5-FU bolus injection was significantly lower than in those that had not. Negative correlation was observed between DPD activity and bolus injection dosage (r = -0.691, p < 0.05). CONCLUSIONS: A bolus injection suppresses hepatic DPD activity and its effects are dependent on dosage, resulting in slower elimination of 5-FU from the blood and contributing to long-term systemic exposure to 5-FU.
Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Dihydrouracil Dehydrogenase (NADP)/drug effects , Fluorouracil/administration & dosage , Liver/drug effects , Animals , Antimetabolites, Antineoplastic/pharmacokinetics , Antimetabolites, Antineoplastic/pharmacology , Dihydrouracil Dehydrogenase (NADP)/metabolism , Dose-Response Relationship, Drug , Fluorouracil/pharmacokinetics , Fluorouracil/pharmacology , Half-Life , Injections , Liver/enzymology , Male , Rats , Rats, WistarABSTRACT
Dissolving microneedles (DMs) were applied to glucose monitoring in the dermal interstitial fluid (ISF) of rats and their potential as an alternative blood glucose monitoring device was evaluated. Sodium chondroitin sulfate was used to prepare DM array chips, which consisted of 300 DMs/cm(2). The mean length of the DMs was 475±18 µm and the mean diameter of the basement was 278±8 µm. After DMs were inserted into the skin of the hair-removed rat abdomen, a wet unwoven cloth containing 10-30 µL of water was placed on the skin and ISF was extracted. By increasing the absorbed amount of water on the unwoven cloth from 10 to 30 µL, the extracted amount of glucose increased from 1.66±0.35 µg to 2.75±0.61 µg. Increasing the adhesion time of the wet unwoven cloth to the skin from 0.1 to 5.0 min, increased the amount of ISF glucose from 1.99±0.13 µg to 5.04±0.38 µg. The relation between the amount of glucose in ISF and blood glucose concentrations was examined. With increase in the adhesion time, the coefficient of determination, r(2), increased from 0.501 to 0.750. The number of DMs also affected the relationship and values of the coefficient of determinations, r(2) were: 0.340 (25 DMs), 0.758 (50 DMs), 0.763 (100 DMs), 0.774 (200 DMs), and 0.762 (300 DMs). These results indicate the usefulness of DMs as an alternative blood glucose monitoring device.
